Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers, where the cancer cells metastasize (spread) from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction, and other symptoms can potentially develop during later stages of the disease.
Rates of detection of prostate cancers vary widely across the world, with South and East Asia detecting this cancer less frequently than in Europe and especially the United States. Prostate cancer tends to develop in men over the age of fifty and although it is one of the most prevalent types of cancer in men, many never have symptoms, undergo no therapy, and eventually die of other causes. However, prostate cancer accounts for approximately 15 percent of all cancer cases in the United States and 15 percent of male cancer deaths. Further, the total cost of treating prostate cancer in the U.S. amounts to several billion dollars per year. Since most men diagnosed with the disease are over age 65 years of age, most of the cost is paid for through Medicare. Thus, although a slow growing cancer, prostate cancer has profound implications for society, and it would be beneficial to detect and treat aggressive cancers as early as possible.
The presence of prostate cancer may be indicated by symptoms, physical examination (e.g., by digital rectal examination or DRE), assay for cancer markers, and/or biopsy. The most widely used and successful serum marker for prostate cancer is prostate-specific antigen (PSA). One reason for the success of this protein as a serum marker is that PSA is present in the prostate tissues at 1 mg per cc of tissue, but is almost undetectable in the serum of men with healthy prostates. The presence of elevated PSA in the serum is thus indicative of prostate trauma or some type of prostate disease.
However, one shortcoming of PSA is that it is also elevated in benign prostate diseases such as BPH and prostatitis. Therefore, efforts to improve the diagnostic utility of PSA have been undertaken, and improvements have come from an understanding of the various molecular forms of PSA in the serum.
It was initially assumed that the PSA measured in the serum was the natural 33 kDa form of the protein containing 237 amino acids. It was only later discovered that PSA in the serum is mostly covalently attached to the serum protease inhibitor alphal-antichymotrypsin (ACT) and that only a relatively minor portion of the PSA was present as the non-complexed form. Thus, the terms “free” PSA (FPSA or free-PSA) and “complexed” PSA (cPSA) are now used to distinguish non-complexed from complexed PSA.
Immunoassays have long been developed to distinguish free and total PSA (free plus complexed PSA) and it is known that a lower ratio of free-PSA correlates with a higher risk of prostate cancer. By contrast, a higher percentage of free-PSA correlates with benign disease such as BPH. Since that discovery, different PSA antibodies have been developed that can distinguish free-PSA from cPSA and total PSA, some of which have been applied in clinical studies.
More recently, the molecular forms of PSA have expanded beyond free and complexed PSA to include the sub-forms of free-PSA-BPSA and pro-PSA. The biomarker BPSA is a form of free-PSA that is identical to native mature PSA, contains 237 amino acids like PSA, but has 2 internal peptide bond cleavages at Lys182 and Lys145. BPSA is elevated in the prostate transition zone and is associated with benign prostatic hyperplasia (BPH), whereas most cancers are in the periphery zone. Pro-PSA is the zymogen form of PSA and increases in cancer. Because BPSA and pro-PSA are associated with opposing disease states in the prostate, they are sometimes referred to as the yin and yang of PSA forms. Together these forms represent individual forms of free-PSA that are more disease-specific than free-PSA or cPSA.
Although the PSA-based tests have improved over time, there is still a need in the art for simple, reliable diagnostic tests for prostate cancer that can be applied in any convenient setting, including for example, retail outlets or drug stores. The ideal test would be reliable, very sensitive, and, in combination with input about various risk factors, be able to differentiate between the various prostate diseases and allow the patient to make informed choices about what next steps, if any, should be taken to address prostate problems.